Fig. 5
Schematic representation of four major molecular lesions in pancreatic ductal adenocarcinoma (PDAC). PDAC is primarily caused by genetic mutations in four genes: an oncogene, KRAS (encoding K-Ras); and three tumor suppressor genes, TP53 (encoding p53, a transcription factor), CDKN2A (encoding p16INK4A, a CDK inhibitor), and SMAD4 (encoding SMAD4, a transcription factor). Constitutively active K-Ras with the G12X mutation leads to increased activation of Raf, MEK, and ERK through a phosphorylation cascade. ERK activates transcription factors such as c-Myc, Elk-1, and c-Jun, leading to cell proliferation. Insulin binding to IR together with active K-Ras initiates PI3K activation. PI3K converts PIP2 to PIP3, leading to mTORC1 activation. This includes AKT activation by PDK1 and mTORC2. mTORC1 phosphorylates S6K1 and 4E-BP1. S6K1 activates rpS6. Phosphorylation of 4E-BP1 removes its inhibitory role on eIF4E, which is involved in translational activation and regulation of cell growth. Inactivation of p16INK4A by mutation or genomic deletion impairs its function as a CDK4 inhibitor, leading to an unregulated cell cycle transition. Inactivation of p53 by mutation hinders its functions, such as blocking of angiogenesis, DNA repair, and induction of apoptosis. p53 mutant also impairs the expression of p21 (a CDK inhibitor), which is involved in G1/S arrest due to damaged DNA. The TGFβ ligand binds to the TGFβ receptor type II (RII) dimer, which recruit the type I (RI) dimer to form a hetero-tetrameric complex. RII phosphorylates the serine/threonine kinase of RI. Under physiological conditions, RI phosphorylates the receptor-regulated SMAD (RSMAD), such as SMAD2 and SMAD3, causing them to dissociate from the receptor complex. The RSMAD complex associates with a common mediator SMAD (coSMAD), i.e., SMAD4, to form a complex that enters the nucleus to bind its target genes, leading to cell cycle arrest and apoptosis. Inactivation of SMAD4 by mutation or genomic deletion impairs its tumor suppressor function in PADC. As discussed in the text, as a highly aggressive cancer, it also involves overexpression of multiple genes, e.g., YAP1, MYC, HMGA2, IGF2BP1 and IGF2BP3, and dysregulation of epigenetics modulators, e.g., HDAC1/2/5, KDM6A, MLL histone methylases, and histone methyltransferases. IR insulin receptor, PDK1 phosphoinositide-dependent kinase 1, 4E-BP1 eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1, IRS insulin receptor substrate
